1. Targeting acute myeloid leukemia through multimodal immunotherapeutic approaches
- Author
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Scott Portwood, Amanda C. Przespolewski, and Eunice S. Wang
- Subjects
Cancer Research ,Innate immune system ,business.industry ,medicine.medical_treatment ,Myeloid leukemia ,Hematology ,Immunotherapy ,medicine.disease ,Immunity, Innate ,Leukemia, Myeloid, Acute ,Mice ,Leukemia ,Immune system ,Oncology ,Interferon ,Apoptosis ,In vivo ,medicine ,Cancer research ,Animals ,Humans ,business ,medicine.drug - Abstract
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a dismal prognosis. Immunotherapeutic approaches using single agent checkpoint inhibitors have thus far shown limited success. We hypothesized that successful adaptive anti-AML specific immune responses require additional modulation of innate immunity. DMXAA exposure resulted in modest apoptosis of C1498 AML cells with a subtle increase in PD-L1 expression and limited production of IL-6 and IFN-β. In contrast, DMXAA + anti-PD-1 ab, but not either agent alone, significantly decreased in vivo disease burden and prolonged overall survival in C1498 engrafted leukemic mice. Combination-treated mice demonstrated increased memory T-cells and mature dendritic cells, lower numbers of regulatory T-cells and evidence of leukemia apoptosis. Furthermore, these effects were associated with markedly increased serum levels of type I interferon (IFN) and IFN gamma. We demonstrate that combining an innate immune agonist with a checkpoint inhibitor synergistically improved anti-tumor activity in a preclinical AML model.
- Published
- 2021